Disorders of water metabolism are common among the elderly, the acutely and chronically ill, and among patients taking certain medications. Abnormal water balance is detected clinically by an increase or decrease in the serum sodium concentration (hyper- and hyponatremia, respectively). Hyponatremia is the most common of the electrolyte abnormalities and even a modest reduction in serum sodium concentration (i.e., water excess) is associated with substantial morbidity and mortality. Rare mutations in water-regulatory genes cause familial abnormalities of water balance; however, these account for only a small minority of cases of hyponatremia. Our preliminary data strongly support the heritability of systemic water balance; in addition, we have identified a non-synonymous polymorphism in a water-regulatory gene that is associated with hyponatremia in several human populations. No prior studies have addressed the genetics of water balance on a population-wide basis and there is at present no way to predict who is at greatest risk from medications or disease states statistically associated with the development of hyponatremia. The over-arching objective of this proposal is to define the genetics of systemic water balance on a population-wide basis using data derived from prior large-scale NHLBI-sponsored (and other NIH-sponsored) cohort and family-based studies. In Aim I, we will quantify the heritability of water balance in additional human populations using data from family-based components of large NHLBI-funded cohort studies. In Aim II, we will identify human genetic polymorphisms associated with aberrant water balance via a candidate gene approach. Banked genomic DNA previously obtained in the course of large NHLBI-funded cohort studies will be used. In Aim III, genome-wide association studies will be performed to identify in an unbiased fashion genetic polymorphisms associated with aberrant systemic water balance in large cohorts. For this Aim, we will use high-density genotyping data generated as part of ongoing analysis in several NHLBI-funded cohort studies. Through this combination of approaches made possible by NHLBI-supported data generation, we hope to elucidate the human genetic basis for systemic water balance and identify polymorphisms associated with hypo- and hypernatremia.